Promiscuous Gene Expression in the Thymus: A Matter of Epigenetics, miRNA, and More?

Autoimmune regulator (Aire) is a transcriptional regulator of peripheral tissue antigens (PTAs) and microRNAs (miRNAs) in medullary thymic epithelial cells (mTECs). In this study, we tested the hypothesis that Aire also played a role as an upstream posttranscriptional controller in these cells and that variation in its expression might be associated with changes in the interactions between miRNAs and the mRNAs encoding PTAs. We demonstrated that downregulation of Aire in vivo in the thymuses of BALB/c mice imbalanced the large-scale expression of these two RNA species and consequently their interactions. The expression profiles of a large set of mTEC miRNAs and mRNAs isolated from the thymuses of mice subjected (or not) to small-interfering-induced Aire gene knockdown revealed that 87 miRNAs and 4,558 mRNAs were differentially expressed. The reconstruction of the miRNA–mRNA interaction networks demonstrated that interactions between these RNAs were under Aire influence and therefore changed when this gene was downregulated. Prior to Aire-knockdown, only members of the miR-let-7 family interacted with a set of PTA mRNAs. Under Aire-knockdown conditions, a larger set of miRNA families and their members established this type of interaction. Notably, no previously described Aire-dependent PTA interacted with the miRNAs, indicating that these PTAs were somehow refractory. The miRNA–mRNA interactions were validated by calculating the minimal free energy of the pairings between the miRNA seed regions and the mRNA 3′ UTRs and within the cellular milieu using the luciferase reporter gene assay. These results suggest the existence of a link between transcriptional and posttranscriptional control because Aire downregulation alters the miRNA–mRNA network controlling PTAs in mTEC cells.

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“…Control of PGE may be more complex and may involve epigenetic mechanisms and posttranscriptional regulation involving miRNAs (5, 28, 33, 34). …”

Section: Introductionmentioning

confidence: 99%

“…Our group demonstrated for the first time that the Aire gene regulated the expression of miRNAs in mTECs (35). Additionally, miRNAs in the thymus were associated with T cell development, posttranscriptional regulation of the Aire mRNA and PGE, maintenance of the thymic architecture, and thymic cellularity (33, 34, 36, 37). …”

Section: Introductionmentioning

confidence: 99%

Aire Downregulation Is Associated with Changes in the Posttranscriptional Control of Peripheral Tissue Antigens in Medullary Thymic Epithelial Cells

et al. 2016

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“…The expression of TRAs is in part under the control of the autoimmune regulator (Aire), but also controlled by the transcription factor Fez2f 56. Aire has also been implicated to be important for antigen transfer from mTECs to dendritic cells (DCs) as well as for regulation of the expression of mTEC specific miRNAs important for TRA expression and TEC maturation78. Antigen transfer from TECs to DCs and thymocytes as well as intercellular sharing of miRNA within the thymic microenvironment might be prerequisites for optimal thymic function.…”

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confidence: 99%

Thymic exosomes promote the final maturation of thymocytes

Lundberg

Berglund

Skogberg

et al. 2016

Sci Rep

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Extensive knowledge has been gained the last years concerning mechanisms underlying the selection of single positive thymocytes in the thymic medulla. Less is known regarding other important processes in the thymic medulla such as the regulation of late stage thymocyte maturation. We have previously reported that exosomes are abundant in the thymus with a phenotype that indicates an epithelial cell origin and immunoregulatory properties. In this study we use an in vitro system to investigate the effects of thymic exosomes on the maturation of single positive thymocytes as well as effects on nTreg formation. We show that thymic exosomes promote the maturation of single positive CD4+CD25− cells into mature thymocytes with S1P1+Qa2+ and CCR7+Qa2+ phenotypes. Furthermore, we show that thymic exosomes reduce the formation of CD4+CD25+FoxP3+ thymocytes and that these exosome effects are independent of dendritic cell co-stimulation but require intact exosomal RNA content and surface proteins. An efficient direct uptake of exosomes by both thymocytes and thymic DC’s is also demonstrated. In conclusion, this study demonstrates that exosomes may represent a new route of communication within the thymus.

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“…It has been shown that miRNAs play important roles in regulating cell death and proliferation during the process of aging [40]. Several studies have revealed that miRNAs are necessary in the maintenance and function of the TECs [36,[40][41][42]. However, whether miR-195a directly regulates TECs function remains unclear.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-195a-5p inhibits mouse medullary thymic epithelial cells proliferation by directly targeting Smad7

Guo¹,

Ye²,

Qi³

et al. 2016

ABBS

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MiR-195 has been implicated in inhibiting cell proliferation in different types of tumors. Whether it contributes to the process of thymic epithelial cells (TECs) proliferation remains unclear. In this study, we found that miR-195a-5p was highly up-regulated in the TECs isolated from the aging mice. Further experiments showed that miR-195a-5p mimic transfection inhibited the proliferation of mouse medullary thymic epithelial cell line 1 (MTEC1), whereas the transfection of miR-195a-5p inhibitor in MTEC1 had the opposite effect. In addition, miR-195a-5p had no obvious effect on MTEC1 apoptosis. Furthermore, Smad7, a negative regulator of transforming growth factor β pathway, was confirmed as a direct target of miR-195a-5p by luciferase assays. Taken together, our results indicate that miR195a-5p inhibits MTEC1 proliferation, at least in part, via down-regulation of Smad7.

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Promiscuous Gene Expression in the Thymus: A Matter of Epigenetics, miRNA, and More?

Cited by 36 publications

References 74 publications

Aire Downregulation Is Associated with Changes in the Posttranscriptional Control of Peripheral Tissue Antigens in Medullary Thymic Epithelial Cells

Aire Downregulation Is Associated with Changes in the Posttranscriptional Control of Peripheral Tissue Antigens in Medullary Thymic Epithelial Cells

Thymic exosomes promote the final maturation of thymocytes

MicroRNA-195a-5p inhibits mouse medullary thymic epithelial cells proliferation by directly targeting Smad7

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